journal papers and · bronchography (which had suggested widespread basal bronchiec-tasis)...

BRITISH MEDICAL JOURNAL 14 AUGUST 1971 391

PAPERS AND ORIGINALS

Lung Transplantation in a Patient with Fibrosing Alveolitis

P. HUGH-JONES, A. M. MACARTHUR, P. A. CULLUM, S. A. MASON, W. A. CROSBIE,D. C. S. HUTCHISON, M. C. WINTERTON, A. P. SMITH, B. MASON, L. A. SMITH

British Medical journal, 1971, 3, 391-398

SummaryThe transplantation of the right lung into a man aged40 who was suffering from cryptogenic fibrosing alveol-itis is described. Before transplantation he had beendependent on oxygen, even at rest, for 24 hours a dayfor almost two years. The donor was a boy of 16 yearswho had had a fatal cerebral haemorrhage. The trans-planted lung functioned perfectly from the time ofoperation until the patient's sudden death two monthslater from an overwhelming haemoptysis apparentlyfrom a small peribronchial abscess rupturing into thepulmonary artery. By the third postoperative weekthe patient had been able to walk unaided and withoutdistress outdoors. The problem of differentiating infec-tion from incipient rejection is discussed. We concludethat clinically successful lung transplantation can beachieved, but only if the problems of lung function,infection, and immunosuppression can all be overcome.

Introduction

Since the first human lung transplant was made eight yearsago (Hardy et al., 1963) we believe that a total of 27 havebeen performed in various countries of the world (OrganTransplant Registry, 1971). In contrast to the accepted thera-peutic value of kidney transplantation for terminal renal

King's College Hospital Medical School, Denmark Hill, LondonS.E.5

P. HUGH-JONES, M.D., F.R.C.P., Consultant Physician and Director,Pulmonary Research Unit

A. M. MACARTHUR, F.R.C.S., Consultant Thoracic SurgeonP. A. CULLUM, F.R.C.S., Consultant Thoracic SurgeonS. A. MASON, F.F.A. R.C.S., D.A., Consultant AnaesthetistW. A. CROSBIE, M.B., M.R.C.P. (LOND., ED.), Lecturer in Medicine,

Pulmonary Research UnitD. C. S. HUTCHISON, M.R.C.P.GLASG., Lecturer in Medicine, Pulmonary

Research UnitM. C. WINTERTON, M.R.C.P., Senior RegistrarA. P. SMITH, M.B., M.R.C.P., Research Assistant, Pulmonary Research

UnitB. MASON, M.R.C.P., RegistrarL. A. SMITH, A.I.S.T., Research Assistant, Pulmonary Research Unit

failure, lung transplantation, with one notable exception, hasnot been of any real value to the patients, though the operationwas nearly always technically successful.

Respiratory failure accounted for most of the early deathsafter operation and infection for nearly all the rest (Wildevuurand Benfield, 1970). Respiratory failure usually arose whenone lung was transplanted into patients with terminal air-flowobstruction because of the very different compliance andairways resistance of the transplanted and the remaining lungwhich produced gross imbalance between the distributionof gas and blood in the two lungs (most of the inspired airgoing to the original lung, but most of the blood to the newone) or the new lung was simply compressed by overinflationof the old. Such blood gas disturbance after operation is atpresent the major contraindication to human lung trans-plantation (Bates, 1970). Infection, both bacterial and viral,was also a major hazard (Hardy et al., 1970) and readily occursin the lung from organisms inhaled by the patient, who ismade vulnerable to their attack because of the immuno-suppression necessary for the transplant, or they may alreadybe present in the donor or in the recipient's remaining lung.Rejection has rarely been the cause of failure, and only 5out of 16 patients reviewed from necropsy studies showedany histological evidence of an immune change (Veith, 1970).There seems to be no reason why a lung graft should not doas well as a kidney graft, provided the postoperative functionaland infective problems are overcome and correct immuno-suppression is given, though the problem of distinguishingthreatened rejection from infection during the critical fewweeks after operation is paramount, and remains one of themajor obstacles to clinical success (Hutchin et al., 1971).Here we present a preliminary account of a transplant

of a right lung into a 40-year-old man who was moribundfrom fibrosing alveolitis of unknown cause. He survivedwith remarkably good lung function for two months afteroperation, though before it he had been completely sedentaryand dependent on continuous oxygen for about two years.We thought lung transplantation to be ethically justified

in his case, in spite of the generally poor previous clinicalresults from the operation, because he had a progressive andincurable disease which had produced, at his relatively earlyage, a state of complete oxygen dependency. Careful assess-ment of the function of both his lungs made us believe that

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he, like the Belgian patient who lived for 10 months afteroperation (Derom et al., 1969), would survive the operationwithout blood gas disturbance. Thus when an uninfectedand well-functioning donor lung became available we recom-mended the operation, to which he agreed, realizing full wellits hazards.

Case ReportThe patient, a 40-year-old Iraqui living and working in London,was first seen in 1966 when he was 36 years old. He had beenwell until the age of 15 years when he noticed clubbing of hisfingers. The clubbing became progressively more noticeable, buthe had no other symptoms till he was about 30 when he developedundue shortness of breath on exertion which had become severeby the time we first saw him. He had had some blood-stainingof his sputum for the previous six months and occasional painsin his joints and some swelling of his ankles. He had always livedand worked in Baghdad, until in the course of his work he went toRussia and Greece and then finally to London. He had had typhoidand malaria in the past and had smoked up to 60 cigarettesa day but had stopped smoking completely about a year pre-viously. He had never been exposed to asbestos or other industrialagents apt to cause pulmonary fibrosis and there was no familyhistory of finger clubbing. He had had radiographs, includingbronchography (which had suggested widespread basal bronchiec-tasis) performed under Professor Farhan Bakir, Dr. Kontaxis, andDr. Alfakhri in Baghdad, where the provisional diagnosis of anunusual variety of interstitial fibrosis, affecting mainly the lowerlobes, had been made. We, too, felt that cryptogenic fibrosingalveolitis was the most probable diagnosis, but in view of hisage, disability, and prognosis it was important to try to make adefinite diagnosis and to exclude other more treatable conditions(such as bronchiectasis causing clubbing and haemoptysis from,say, hitherto unsuspected achalasia of the oesophageal cardia, orpulmonary schistosomiasis) and to exclude the possibility of analveolar cell carcinoma having arisen. Thus in 1966 he had thefollowing investigations.Radiology.-There was fine nodulation in both lung fields,

maximal in the middle and lower zones, with the diaphragmsraised and the lesser fissure depressed, so that most of the lungfield represented the upper lobes (Fig. 1). Bronchography was notrepeated.

FIG 1.-Posteroanterior chest radiograph before operation.

Laboratory investigations excluded schistosomiasis and otherconditions unusual in Britain.

Overall Lung Function.-The results (Table 1) show the typicalchanges of stiff lungs, with a gas transfer deficit, giving a low car-

BRITISH MEDICAL JOURNAL 14 AUGUST 1971

TABLE i-Overall Lung Function Tests in 1966

PredictedNormal

FEV, (litres)... 1-84 3-6VC (litres) . .21 4-2FEVIVC (,,) . .87 About 75Tco(ml/mm Hg/min) .90 29-5Static lung compliance (1./cm H20) .007 0 3

Exercise Test (maximum=300 kg-m/min)Resting Exercise

VE (litres) . .19 62VA (litres) . .9 45Pao. (mm Hg) .76 46Sao2 (°') 95 78A-ao2 diff. (mm Hg) 40 64Paco, (mm Hg) . .33 33

bon monoxide transfer (Tco) and hyperventilation associated witha fall in arterial oxygen tension and a large alveolar-arterialgradient for oxygen on exercise.

Regional Lung Function at Bronchoscopy.-This was measuredwith a mass spectrometer, with the bronchoscopy performed underlocal anaesthesia (West, 1960; Hugh-Jones, 1967). The bronchialtree appeared anatomically normal, but the gas flow into bothlower lobes was grossly reduced so that about 85 ,% of the venti-lation was going to the two upper lobes, while the blood flow tothe lower lobes was even more reduced, giving the characteristicB pips on the spectrometer 02 and CO0 traces (West and Hugh-Jones, 1959).

All the above investigations pointed to a severe, progressive,fibrosing alveolitis of unknown cauce, almost obliterating thefunction of both lower lobes of the lungs but partly sparing theupper lobes. After careful consideration thoracotomy was advisedfor open lung biopsy; firstly, to prove the diagnosis (and excludecomplicating alveolar cell carcinoma so far as possible), and,secondly, because it might be possible to remove a source ofhaemoptysis or conceivably, by lower lobectomy, to improve themechanics of the lung if the upper lobes were largely free fromthe disease process. At thoractomy on 30 Tuly 1966 there was afree pleura, but the right lower lobe was shrunken to about halfnormal size and poorly aerated. It was impossible to inflate itfurther by vigorous inflation through the endotracheal tube. Itfelt rubbery but coarsely granular. The upper and middle lobeswere similarly affected, but much less severely. There was noindication for lobectomy so a biopsy was simply taken from theposterior basal segment of the lower lobe. Histology was typicalof a fibrosing alveolitis with pronounced squamous metaplasia ofthe bronchial mucosa.

Preoperative Course

Following these investigations in 1966 he was put on 15 mg ofprednisone daily and weight reduction was recommended with alow calorie and low carbohydrate diet. In spite of these measuresboth his lung function and clinical state deteriorated and by1967 he was started on potassium para-aminobenzoate as well asthe prednisone and given a portable oxygen set so that he couldcontinue working at the Embassy. His resting arterial Po2 was53 mm Hg falling to 39 mm Hg on gentle walking, though withthe portable oxygen set the figures were, respectively, 76 and 60mm Hg.By 1969 we started him on 50 mg of azathioprine a day as well

as the prednisone which he maintained until the transplantoperation in an effort to halt the relentless progress of the disease.Following the success of the Belgian lung transplant, we con-sidered the possibility of transplant for him at a later date, thoughhe was then still working daily and using portable oxygen. By1970 his FEVy had fallen to 1-4 1., his vital capacity to 1-5 1.while his total lung capacity remained at about 2 5 1. with anFRC of 1-3 1. and RV of 0.9 1. The CO transfer was impossibleto measure but he extracted only 6% per breath of the carbonmonoxide in a mixture with air. His E.C.G. had shown slightright ventricular hypertrophy with an S wave dominant in allprecordial leads. Though his haemoglobin remained raised at 18-2g/100 ml, his blood volume, measured by Professor W. M. David-son and Dr. P. Flute using (125I-albumin), was 4.7 1. but the redcell mass of 195 1. was within the normal range of 31 ml/kg.



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BRITISH MEDICA JouRNAL 14 AUGUST 1971

He was finally forced to stop all work for about two yearsand became dependent on oxygen for 24 hours a day. During thefew months before transplant it became difficult to supply himwith enough oxygen even at complete rest, he had difficulty ineating or in cleaning his teeth, and he became deeply cyanosedand exceedingly breathless if he took the mask off. Eventually hewas consuming no fewer than twenty 100 ft3 (2-83 m3) cylindersof oxygen a week. He was admitted to hospital moribund from aminor chest infection two weeks before transplant but recoveredwith antibiotics. He became so cyanosed and breathless withoutoxygen that it was then impracticable to measure his arterial bloodgas tension breathing air.

Lung DonorAfter the patient accepted the possibility of lung transplant andhad had his blood group and tissue type recorded (with the helpof Professor Davidson and his staff, and through Professor R.Batchelor and Mr. M. Bewick of Guy's Hospital) he said he had"died" from all useful life two years ago and was willing to acceptthe risk. He waited nine months for the operation. We had hopedfor a lung, from a cerebrally dead patient, which had been venti-lated for less than 24 hours, which was a good tissue match, waswithout obvious infection, and appeared, clinically, to be function-ing well. Only four lungs of a compatible blood group becameavailable during the nine months: the first we refused on groundsof tissue typing, the second because of infection and poor clinicalstate, and the third because of the old age of the donor and theclinical state of the lung.

At about 5 a.m. on 26 March 1971 a boy aged 16 years wassent to this hospital after he had been found unconscious on thefloor following an intense headache and vomiting. He was said tohave had a similar intense headache about a week before. Onarrival his breathing had stopped but his heart was still beating sohe was immediately ventilated. Lumbar puncture produced heavilyblood-stained cerebrospinal fluid. He was transferred to the in-tensive care unit but there was no improvement in his condition,and his pupils remained dilated and fixed. The physicians incharge considered him to be cerebrally dead by 9 a.m. but soughtthe opinion of the consultant neurologist, who agreed. His electro-encephalogram showed no response. Subsequently, when therewas no possibility of resuscitating the patient and as a possibledonor role was then considered, both a further electroencephalogramand a cerebral angiogram were done that afternoon. The lattershowed that there was no cerebral blood flow at all. Only whenthe physicians in charge of him had no doubt whatsoever aboutcerebral death for many hours were the transplant team notifiedand the permission of his relatives sought early that evening touse organs. The coroner was then informed when this permissionhad been given.The recipient's blood group was B positive, the donor's 0

positive; the recipient's tissue type HLA 2, 3 on one sublocus withtwo unknown factors on the other; the donor's tissue type HLA 8and BB on one with 2 and an unknown on the other. Thus therewere potentially three major mismatches unless the homozygousstate or common missing factors meant only two. Though thetissue match was not as good as we would have liked, the excellentstate of the lung, short time of ventilation, and lack of infection,together with the hazardous clinical condition of the recipient andthe paucity of potential donors, determined us to recommend thetransplantation to the recipient. This he agreed to.

OperationBy 8 p.m. the transplant team, operating theatres, pump oxy-genator (in case of need), and respiratory laboratory were ready.Anaesthesia.-The problem was how to anaesthetize a patient

who was dependent on pure oxygen inhalation, at rest, for sur-vival. A left Robertshaw double-lumen intratracheal tube wasaccepted so that the patient could use both lungs until perfusion,but the anaesthetist could inflate one lung thereafter, as required.The only premedication was 10 mg of diazepam subcutaneouslyto allay anxiety, given at 8.35 pm. The anaesthetic was startedat 9.20 p.m. and induced by methohexitone 80 mg with suxa-methonium chloride for insertion of the double-lumen tube.Anaesthesia was continued by intravenous phenoperidine andpancuronium bromide as the relaxant.

393

OPERATIVE PROCEDURE

The recipient's chest was opened through the previous thoracotoinyscar and the lung approached through the fifth right intercostalspace. After arterial blood gas results, cardiopulmonary bypass wasagreed to be necessary and this was established with a Temptroloxygenator (right atrium to left femoral artery) with flows rangingfrom 1 to 3 l./min. The patient's condition immediately improvedand the right lung was then excised at the hilum. It was grosslyshrunken and looked and felt not unlike a hobnail liver. Whileall this was proceeding in the theatre, the donor lung was removedin another room after the ventilator had been stopped and cardiacstandstill had takn place to comply with medicolegal requirements.The donor lung was implanted, and arterial, venous, and bron-chial anastomoses were carried out in that order. Because of pro-nounced dilatation of the pulmonary artery the main trunk of thedonor lung was anastomosed end to end to the recipient arterydistal to its first upper lobe branch. The veins were anastomosedwith an atrial cuff from the donor which had to be trimmed to fitthe rather small left atrium of the recipient. A continuous mat-tress suture (Ethicon 6591) was used and all air aspirated beforeremoving the clamps.

After completion of the vascular anastomoses the clamps wereremoved and the bronchial anastomosis was carried out. This wasperformed with interrupted stitches of Tevdek 79-716 with thesuture line made at a point about 1 cm from the upper lobebronchus and 1 cm from the tracheal bifurcation. Disproportionwas again a problem but was overcome by making a long obliqueanastomosis. No attempt was made to preserve bronchial bloodsupply, and the anastomotic line was covered by mediastinal pleura.The implanted lung inflated easily and the patient came off bypasswith no difficulty. The chest was closed with apical and basal drains.The total time of perfusion at normal temperature was 114 minutes,and the warm ischaemic time till blood flow was re-established inthe donor lung was 59 minutes.

OPERATIVE COURSE

While anaesthesia was being induced at 9.20 p.m. with the patientbreathing oxygen he had a Pao! of 59 mm Hg (Sao2 83%), Pco2 of83 mm Hg, and pH 7.2. After taking bacteriology swabs of histhroat, nose, rectum, eyes, and urine he entered the operatingtheatre at 10.15 p.m. and the ventilation was increased to no lessthan 14 l./min of pure oxygen, yet his arterial blood gases werePO2 112 and Pco2 78 mm Hg. With the lung retracted and thechest open the Po2 fell to the very low figure of 39 mm Hg so thatbypass was inevitable. Once established the Po2 rose to 65 (satu-ration 93%) and the Pco2 fell to 49 mm Hg. His right lung wasremoved by midnight and the new lung was in place by 12.15a.m., when ampicillin and cloxacillin were given intravenously.The new lung was re-perfused at 1 a.m. and he came off bypassat 1.40 a.m. On his new lung, ventilated with oxygen, he had asaturation of 97%, Pao2 88, Pco2 34 mm Hg, and pH 7-45. By3.45 a.m. the pancuronium was reversed and he breathed oxygenspontaneously, with the endotracheal tube in, giving blood gasvalues at 3.54 a.m. of Sao2 98%, P02 134, Pco2 75 mm Hg. At4.15 a.m. he was conscious and responding to speech but theanaesthetic tube was left in. By 4.45 a.m. he was losing bloodfreely from the thoracic drain so he was re-anaesthetized and thechest reopened at 4.50 a.m. By then he was hypotensive with asystemic pressure of 30 mm Hg and a C.V.P. of -5 cm H20after the bleeding. By 6 a.m. the chest was closed again and arepeat chest x-ray film was satisfactory. The anaesthetic tube wasremoved at 6.35 a.m. when he was breathing spontaneously, talk-ing, and passing urine satisfactorily, and he was returned to theward with oxygen by mask. He had had a measured total bloodloss of about 6-5 1. which was replaced by 8 1. of acid-citrate-dextrose stored blood.

Back in the ward at 8 a.m. and breathing 7 I./min pure oxygenby mask spontaneously, he had an arterial oxygen saturationof 95% (Po2 80, Pco2 60 mm Hg, pH 7-31). He was again losingmuch blood through the chest drain so fresh frozen plasma and6 pints (3-4 1.) of fresh blood from relatives was later given. Bythe evening his breathing rate had gone up, from 25/min thatmorning to 60/min and it was evident that blood dot was re-stricting his new lung. Thus his chest was reopened at 9.45 p.m.and the clot evacuated. It was then possible to give him a mixtureof 50% O0/N20 to breathe and his saturation remained at



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95% with a Pco2 of 50 mm Hg and he was finally returned to theward by 10.40 p.m. on 27 March.The pulmonary anastamoses were found to be intact on both

occasions when the chest was reoponed, but on the first somebleeding came from the inferior pulmonary ligament, and on thesecond the skin wound oozing ceased after the transfusion of freshblood.

Postoperative CourseThe patient's ward was a room with adjoining bathroom, bothwith filtered positive-pressure ventilation. All staff before enter-ing changed their clothes for sterile ones, scrubbed, and woresurgical masks and all equipment taken in was gas sterilized.Food, supplied to us from Hammersmith Hospital, had beenmade bacteriologically sterile by neutron irradiation. Daily radio-graphs were taken by inserting the x-ray tube through a polyethyl-ene bag into the room.We have attempted to chart the salient points in his post-

operative course in Fig. 2. The clinical grade presented at thetop of the figure represents an independent assessment by themedical staff and the physiotherapists who visited him daily.There was never disagreement by more than one grade betweenthe two. In the few cases where there was such a difference, thelower grade is recorded. The basis is shown in Table II.The result of the transplant can fairly be said to have been

excellent. From the patient we knew before transplant at clinicalgrade 5 (Fig. 3), he was, by the third day, breathing quietly andhad a normal colour without oxygen. He was able to walk aboutthe room by the fourth day. Initially, he tended to feel panickedwithout the mask, so dependent had he become, even though hisblood gases were satisfactory. By the middle of the fourth weekhe was taken for a drive into the centre of London and subse-

Day 3 5 7 9 11 13 15 17 19 21 23 25 27 29 31 33 35 37 39 41 43 45 47 49 51 53, 9 . ... . . . . .

Transplint -.0. _ L L i LRe-op *ll

Sputum ++ Walking king250-.() outside outs(ide

Clin~ical qradcD

++

500

400 Max.tem eriture (°C

36-- t ~ < 9 < t

25 6 - T+ ++ T4 @14+ T ++ T+

1006

4J Rbsette test (t itre)..

60L x x A X4xj*)

-5 4 0 W.Bg s (W) jLYMph ctes (L) (x10))200]D

CL111 C1 lE T Cn l9(m A PIG A

bihl°nltlniludIllUILinlJ400- OrltlIIl I I

30*1 dtsoe(

FIG. 2-Summary of postoperative clinical course. At top: L=Periods ofappearance of presumed thymic lymphocytes and incipient rejection.INF=Chest infection. D=Severe mental depression. For other detailssee text. At bottom: A=Ampicillin. CA=Carbenicillin. CE=Cephaloridine.CL= Cloxacillin. P= Penicillin. T=Tetracycline. In Rosette test: 0 orabove is optimum supression. N=Normal range. -0-0-0 = TotalW.B.C.s. -@-@-S-@= Lymphocytes.


TABLE u1--Clinical Grade used Postoperatively

Grade 1: Feels well. Able to walk without oxygen and without distress. Feels ableto go outside.

Grade 2: Tired btut otherwise reasonably well. Slight breathlessness. Mainlysedentary.

Grade 3: Confined to bed. Wanting to use oxygen.Grade 4: Breathless and distressed. In bed. Feeling ill. Needing oxygen.Grade 5: Oxygen-dependent at rest. Severely distressed and cyanosed without

oxygen.

FIG. 3-Completely oxygen dependent just prior to operation.

quently for a short walk in a local park (Fig. 4). Six weeks after theoperation he walked briskly up steps and about a quarter of amile (400 m.) without breathlessness to see a new flat to whichwe had hoped to discharge him.On the other hand, his postoperative course was complex, as

Fig. 2 shows, and he had many periods of illness. The true causeof these ill periods we cannot know. We have given our inter-pretation of them in Fig. 2 above the clinical grade. Here Lrepresents our belief that he was producing thymic-dependentlymphocytes active against the graft, and treatment prevented pro-gress towards rejection, while INF represents a period of infection,likewise treated. The treatment given is shown in the bottomtwo parts of the figure. Our interpretation is based mainly on thecombination of the changes in the. clinical grade and the rosettetest, total white cell and lymphocyte count, temperature, andarterial oxygen tension breathing air as shown, together with otherinformation such as chest signs, haematology, sputum culture,biochemistry, and daily radiographs.

IMMUNOLOGICAL CHANGE

This was mainly assessed by the rosette test (Munro et al., 1971).The results shown in Fig 2 represent the titre of lymphocytesuppression, so that a high titre, at or above the optimum lineshown, represents satisfactory suppression, whereas a fall into thenormal range or below means inadequate titre measurements. Thenumber and qualitative character of the lymphocyte rosettes werevisually determined and the appearance of lymphocytes believedto be associated with incipient rejection was noted. These arerecorded as a T+ in Fig. 2. It can be seen that on the threeoccasions shown at the top of Fig. 2, on about days 6, 18, and 28,there is the combination of (1) a low titre in the rosette test withthe appearance of T lymphocytes, together with (2) a rise in theabsolute number of circulating lymphocytes (though the latterwere not recorded on the first occasion), (3) a fall in clinical grade,(4) a low Pao2 breathing air (though the latter was not recordedon the second occasion), and (5) persistent rhonchi in the rightchest on two occasions. This same combination of factors may bepresent on day 37 but not so definitely.Each time this combination of factors occurred the incipient

possibility of rejection was presumed and treatment given (thoughat no time was there any of the hilar flare on the chest x-ray film



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believed to be characteristic of rejection). On the first occasiontreatment was simply an increase in the prednisone and theazathioprine since actinomycin-C was being used concurrently. Therosette test appeared to respond slowly and the patient coincidentallyimproved. On the second occasion antilymphocytic globulin(A.L.G.) became available and reliance was placed on this (andazathioprine with prednisone). On the third occasion, when thepresumption seemed very definite (in view of the ill and severelymentally depressed patient whose rosette test suddenly showedalmost total lack of suppression and abundant T lamphocytes), hewas given up to 0 5 g of intravenous prednisone and the A.L.G.that he was then receiving was doubled. On the more doubtfulfourth occasion, when he had had a high unexplained fever forthree days and there was no certain evidence of infection, norresponse to antibiotics, he was treated on two successive days with1 g and 0 75 g respectively of intravenous prednisone.

USE OF IMMUNOSUPPRESSANTS AND A.L.G.

We had intended to follow the regimen successful in the Belgiancase using an average of 200 mg of azathioprine daily with 40-60mg of prednisone orally and actinomycin-C 200 mg daily for thesecond week and, thereafter, once weekly. We initially had nosatisfactory source of A.L.G. But by the 15th day we were worriedby a fall in the total white cells so stopped the azathioprine (in-correctly, we believe in retrospect), fearing its delayed action, andat the same time reduced the prednisone not only because ofglycosuria but because the patient had had a definite chest infectionfrom about the 9th to the 14th day.

Because of these difficulties with the drugs and because thelymphocytes appeared not to be differentially suppressed relativeto the total white cells an urgent search was made for A.L.G.which we believed to be both effective and safe. Finally, when weapproached Sir Michael Woodruff he authorized Dr. David Long,of Messrs. Burroughs Wellcome Ltd., to supply us with someof their clinically tested T.D.1 batch of horse A.L.G. This wasstarted on day 18 (just as the rosette test was deteriorating) inthe manner suggested by the manufacturers-on the first day at10 mg/kg intravenously (with chlorpheniramine and hydrocortisonein the drip to minimize reactions) and, when that was takenwithout undue reaction, it was given on subsequent days at thefull dose of 20 mg/kg, though on three occasions (during the periodof the very definite lack of active lymphocyte suppression) the dosewas doubled.

FIG. 4-With his brother (right) three anda half weeks after right lung transplantation.

On no occasion, save one, was there a very alarming reactionto the infusion of A.L.G., though distressing shivering or rigorsoccurred after the infusion in spite of the antihistamine drug andhydrocortisone. These rigors were controlled by 20 mg ofchlorpheniramine intravenously, but diazepam, which had been

395

recommended, was without effect. The one bad reaction was whenA.L.G. had appeared to be tolerated well by infu"ion and anattempt was made to give it as a diluted intravenous injection,exceedingly slowly from a syringe. It was stopped after 16 daysbecause a high anti-horse-serum titre was being produced, asestimated by Wellcome Research Laboratory, and though therewas considerable horse IgG circulating its lymphotoxic efficacywas doubtful and there was worry about the possible effect ofthe horse serum reaction on the kidneys. The excretion of theA.L.G., labelled with iodine-125, measured by Mr. M. Clark of thedepartment of medical physics, suggested it was eliminated in twodays, but the' measurement of the in-vivo circulating horseglobulin by the Wellcome Research Laboratory suggested it re-mained almost three times that long. It was for this latter reaFonthat it was considered safe to repeat the infusion during thepossible lymphocytic crisis on day 37.From just before the end of the A.L.G. administration we

attempted to keep the azathioprine constant at 200 mg/day and theprednisone at 40 mg orally with added large transient intravenousdoses of prednisone should incipient immunological reaction besuspected. Professor A. G. R. Sheil, of the University of Sydney,Australia, generously agreed to supply us with some of their goatA.L.G. (Sheil et al., 1971) which arrived by air on day 50, but wasnever used.

INFECTION

From previous accounts of human lung and kidney transplantswe feared not only bacterial infection in the lungs, especially frompseudomonas, but virus infections and infection from less commonpathogens. Swabs of the donor lung were sterile, the recipientappeared relatively free from lung infection at the time of trans-plant, and after the operation we attempted to maintain a sterileenvironment. There was only one definite period of infection, fromabout the 9th to the 14th day, when the sputum was increased inamount, frankly purulent, and growing Pseudomonas aeruginosa onculture, and the chest radiograph showed what appeared to be asmall area of collapse consolidation below the lesver fissure in thenew lung. He was treated with gentamicin (40 mg intramuscularlythrice daily) together with cephaloridine (1 g intramuscularly twicedaily) and subsequently teracycline instead (2 g orally/day). Hisfever fell and his clinical condition was excellent by day 14 sothat the antibiotics were all stopped. Unfortunately, the feverstarted to rise again the next day so carbenicillin was substituted,because of reported resistance to the other antibiotics. at firstintramuscularly (2 g four times a day for two days) and then, witha further rise of fever and pronounced deterioration in his generalclinical condition to grade 4 (Fig. 2), 30 g/day intravenously withcolistin inhalations as suggested by Pines et al. (1970).

In retrospect, and subsequently, we believe his state was fromimmune reaction and it improved remarkably soon after startingthe T.D.I. horse A.L.G. Again on the 27th dav we fearedpseudomonas infection and restarted intravenous carbenicillin andcolistin inhalations, but again, in retrospect, we believe this mayhave been an immunological deterioration.We were concerned by his persistent bouts of fever (Fig. 2), and

becau-e of a blood culture growth first of a coagulase-negativestaphylococcus in three bottles after one day (day 36) and thenof Streptococcus faecalis (day 39) he was given penicillin(4 megaunits intravenously then 2 megaunits intramuscularly withcloxacillin 8 g/day orally) and ampicillin for the two findingsrespectively. We realize that these organisms could have beencontaminants, but from the results of skin swabs of patient anddoctors and because of the risks under immunosuppression wegave the antibiotics. There is now little doubt that his fever fromday 35 to day 53 was caused by a pyaemia.

CHEST X-RAY EXAMINATION

The remarkable and gratifying feature of the daily postoperativechest radiograph (Fig. 5) was that there was no definite changesince the time of transplant (apart from the small area of collapseconsolidation between about days 9 and 14) and there was atransient increase in the small effusion under the wound andin the lesser fissure which disappeared after aspiration. Theoriginal lung remained contracted while the new lung was wellexpanded and showed a good excursion between insoiratory andexpiratory films. But on day 52 an air pocket appeared near the



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396

medial aspect of the bronchial suture line, on tomographs, andwe feared a peribronchial abscess.

LUNG FUNCTION

He had clear vesicular breath sounds over the new right lungthroughout, with added persistent rhonchi on only two occasions,noted above, when we suspected incipient rejection. Over the leftlung they were likewise clear in the upper third, but almost in-audible below where the original loud crepitations persisted. Hisarterial blood oxygen at rest and breathing air is shown in Fig. 2.The highest oxygen tension was recorded on day 40 and the

arterial blood that day showed a saturation of 96%'o, Po2 76 mm Hg,Pco2 32 mm Hg, pH 7 49, and plasma bicarbonate 32 mEq/1. HisFEV1 on the 45th day was 1-6 1. with a VC of 19 1., FEV/VC ratio84%, while his carbon monoxide transfer was 14-2 ml/mm Hg/min (predicted normal 28) with a Kco value of 3 0. A-technetium-99m-labelled albumin scan (Fig. 6) on days 15 and 30 with agamma camera was similar on the two occasions. It showed that thenew lung had all the perfusion except for some to the apex of theold one. A xenon-133 scan, done at Hammersmith Hospital on day46, showed that the ventilation was distributed in balance with theblood and in the new lung both had a virtually normal distributionfrom apex to base (West, 1963). This finding was compatible withthe clinical, radiological, and arterial blood gas results.

FIG. 5-Posteroanterior chest radiograph on day 8.

ELECTROCARDIOGRAM

Immediately after the transplant a right ventricular strain patterndeveloped but disappeared over the next few days. There was

subsequently little change until the 38th day, when a transientatrial tachycardia was seen associated with flattening of T wavesover the precordial leads.

METABOLISM AND ELECTROLYTES

Following the high dose of oral steroids given for immuno-suppression (we now think, incorrectly) the patient developedglycosuria and a raised fasting blood sugar level (which was easilycontrollcd by small insulin doses) and then a high loss of urinarypotassium (rising to 158 mEq in 24 hours), which in spite of oralpotassium supplements caused a fall of serum potassium. Thesedifficulties ceased when the oral prednisone was reduced on the10th day.

HAEMATOLOGY

In spite of the inuunosuppression the daily platelet count was


never seriously depressed. On the other hand, the haemoglobin,which was 18 g/100 ml before transplant, steadily fell during thefirst 10 postoperative days, from a constant level of about 15 g toabout 11 g throughout the second, third, and fourth weeks andfinally to the lowest level of 9 g on day 40, when he was givena transfusion of packed cells with improvement both in thismeasurement and in his general condition. From records of thepacked cell volume and a knowledge of the considerable volumeof blood which had to be taken for the necessary control of treat-ment most of the fall, but not all, could be accounted for fromhaemodilution and iron loss, in spite of the administration of oraliron tablets.

His Westergren E.S.R. remained below 20 mm/hr during thefirst two weeks and thereafter showed a steady rise, with somefluctuation, to over 100 mm/hr on some days during the last twoweeks.

FIG. 6-Technetium-albumin scan taken with gamma camera onthe 30th postoperative day showing virtually all the blood flowgoing to implanted right lung.

CAUSE OF DEATH

From day 35 the patient had been having a fever which persistedin spite of antibiotic treatment. However, it fell on day 53 and hefelt much better that evening but he had a sudden severehaemoptysis at 11 p.m. This rendered him unconscious, he wasthen ventilated but at 4 a.m. he had a second and overwhelminghaemoptysis which caused his unexpected death. The full post-mortem findings are not yet complete but the pathologists (Dr.K. B. Shilkin from King's College Hospital and Professor LynneReid from the Institute of DiEeases of the Chest) were able tofind a small fistula from the bronchus to the pulmonary arterypresumed to arise from a peribronchial abscess. The full findingswill be published later.

Discussion

This patient, who survived two months after his transplant,was the second longest survivor, the longest being the Belgianpatient who survived 10 months and was discharged frominpatient care. The transplanted lung in our patient functionedclinically well, and from general and regional tests virtuallynormally, so that his sudden and unexpected death was agreat disappointment. This is especially so because it wasfrom a minute peribronchial abscess which one would normallyexpect to rupture into the bronchus and be discharged andnot, as it happened, to perforate into the pulmonary artery.Moreover, the pyaemic infection was being controlled, thefever had abated on the day of his death, and we had confidentlyexpected to release him from hospital. But even this much was



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worth all the effort-for him as a patient and, in experience,for ourselves. We now feel confident that lung transplantationcan succeed in carefully selected cases. The patient wasresuscitated from an incurable and progressive alveolar fibrosisfrom which he was suffocating from lack of oxygen, and thepractical problem of providing him with enough oxygenwas becoming impossible. To see him directly after operationbreathing freely without oxygen and with a normal colourwas remarkable, and when he left hospital during the fourthpostoperative week to walk about outside with no breathless-ness, he remarked that it was the first time he had worn clothesin 18 months and he felt he was alive again after many years.Our results depend on much previous work by others in

animals and in man, and especially on the pioneering firsthuman lung transplant (Hardy et al., 1963) and on the successof the Belgian case (Derom et al., 1969). We believe thatour patient was clinically successful because extensive pre-operative tests of lung function had shown the nature of hisrestrictive lung disease, so that we were confident that hisown left lung would not become overdistended; becauseextreme care was taken to avoid introducing infection; andbecause we benefited from the experience in kidney andliver transplants of how to deal with rejection which wasanticipated from daily observation of the reaction of thecirculating lymphocytes by the rosette test. Even so, infectionproved to be the obstacle to success.Our case, like the Belgian one, showed that the patient's

new lung could accept, without damage, the high perfusionfrom the moment of transplant caused by the high vascularresistance in the remaining lung. This was probably becausethe new lung was from a young donor and undamaged, sincethe experience of others has been different (Stevens et al.,1970). Our patient showed only a transient pattern of rightventricular strain on the electrocardiogram.We experienced the problem of differentiating infection

from incipient rejection common to all transplant patients.Clinical deterioration can be caused by either, and the tendencyhas been to increase the immunosuppressive regimen at theexpense and risk of infection. Though we were initially indoubt about the interpretation and value of the rosette test,experience made us believe it to have been invaluable foranticipating rejection. We understand that in renal transplantsrosette deterioration precedes loss of kidney function by upto 24 hours, but time must elapse for urine collection. Itmay well be from our results that a fall in arterial oxygentension which can be measured immediately is an early warningsign of incipient rejection, though we, unfortunately, tookinsufficient samples, especially during the second week, torelate this to the rosette test. A fall in tension may also occurwith pulmonary infection.We attribute the avoidance of infection initially to the careful

removal of as much chance of infection as possible by theaseptic condition in the ward, to no artificial mechanicalventilation, to daily physiotherapy, and to insisting that thepatient breathed a high flow rate of filtered air or oxygenby mask when moving about the hospital and only breathingwithout this in the ward or outdoors. We would, in future,avoid giving as much steroid systemically as we did in thispatient.

In retrospect, the immunosuppression seems to have beenreasonably satisfactory and to have prevented rejection, thoughwe would now not give such high oral doses of prednisoneduring the first 10 days but would rely on large intravenous"shots" which are lymphocytotoxic and quickly eliminatedfrom the body (Bell et al., 1971) when the lymphocytes givewarning of rejection. The T.D.1 A.L.G. seems to have beeneffective and the patient was very well soon after its adminis-tration was begun, though we have no proof of its efficacy.It seems that the recommended dose of 20 mg/kg differentiallyreduced the lymphocytes but was not enough to prevent apotential rejection crisis on day 28, though the latter respondedeither to doubling the dose of A.L.G. or to intravenous

397

prednisone injections. Further clinical trials of this A.L.G.seem warranted, but we could not afford to distinguishbetween its effect and that of prednisone in our lung transplantpatient. Such a trial would have to be made in a renal trans-plant patient who could be put on the artificial kidney andlater retransplanted from cadaver sources if irreversible rejectionoccurred.One very important aspect of lung transplantation is the

psychological effects. Not only must the patient be preparedfor the psychological problems of having a foreign organ,but he must be prepared for the isolation, the discomfort ofoperation, and especially for multiple venous and arterialpunctures. In future we would consider making a Scribnershuntatthe time ofoperationto avoid the repeated venepunctures.Our patient was introduced to the isolation ward and thestaff as soon as the operation was envisaged. His fortitudeand emotional stability were admirable. Television, etc.,act only as diversional treatment, and psychotherapy maybe important. Our patient was seriously depressed on aboutday 27 and 28. This could have been organic, from steroids,the immunological effects within his body, or psychogenicbecause, from going about London and feeling well, he wassuddenly confined back to his room and had to endure furtherinfusions when his veins were already painful from carbenicillin.The depression, during which he threatened to dischargehimself, rapidly cleared either because of explanation andpsychotherapy or because of the effect of the immunosuppres-sion on his bodily state.

Conclusion

We conclude that lung transplantation in man will succeed,but until there is more basic knowledge about immunology,the preservation of lungs, and other problems it should bedone only in most carefully selected circumstances. Even thenit must not be lightly undertaken. The surgery itself is onlyone part of the problem, and for success it demands immensetime and the co-ordination of the resources in many differentfields: respiratory physiology, immunology, bacteriology,haematology, biochemistry, radiology, physiotherapy, andpsychotherapy.

Four types of patient might benefit from transplantation.Terminal cases with progressive fibrosis (like our own andthe Belgian case); patients with paraquat poisoning (likethe Edinburgh case) if the poison has been eliminated;progressive pulmonary hypertension; and, finally and mostinteresting, advanced emphysema in young patients such asthose suffering from o-antitrypsin deficiency. The lattercannot be mimicked by animal work, and human experiencehas revealed its problems (British Medical Journal, 1970;Bates, 1970). We believe that by mass spectrometer samplingof the two lungs the ventilation-perfusion balance could bemaintained directly after operation, and it is possible that inman the contralateral lung can be removed once the newlung is established. The transplantation of one lung in animalsafter simply anastomosing bronchus, pulmonary artery, andan atrial cuff with the pulmonary veins to the left atrium,without bronchial artery or lymphatic anastomosis, has beenshown to be compatible with prolonged life and good functionin many reports ever since the first successful mammaliantransplant about 20 years ago (Juvenelle et al., 1951), providedthe warm ischaemic time is kept short and adequate immuno-suppression is given with azathioprine in allo-transplants.

If both lungs are transplanted or one transplanted and theother removed in animals then breathing is severely disturbedfrom alteration of respiratory reflexes, or pulmonary oedemacan occur from the sudden blood flow into one lung. It remainsto be shown whether this is true for man.



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398 BRITISH MEDICAL JOURNAL 14 AUGUST 1971

We are grateful for help from Dr. J. Laws, Professor A. C.Cunliffe and his staff, Professor J. R. May, of Brompton Hospital,Dr. P. Croydon, of Messrs. Beechams Laboratories, Dr. S. Oram,Dr. P. Kidner, Professor C. H. Gray and his staff, and ProfessorW. Davidson and his staff. Many others helped us, especially thenursing staff and physiotherapists of King's College Hospital andthe technical and secretarial staff of the pulmonary research unit.We wish to thank the Board of Governors and administrative stafffor giving permission for this operation in a busy general hospital.Professor Lynne Reid, of the Brompton Hospital, has kindlyagreed to do detailed pathological studies of the excised lung. Weare especially indebted to Mr. M. Bewick, of Guy's Hospital, notonly for the daily rosette test but for continued helpful adviceabout the immunosuppressive treatment.

References

Bates, D. V. (1970). New England Journal of Medicine, 282, 277.Bell, P. R. F., et al. (1971). Lancet, 1, 876.

British Medical Journal, 1970, 3, 600.Derom, F., et al. (1969). 7ijdschrift voor Genceskunde, 25, 109.Hardy, J. D., Webb, W. R., Dalton, M. L., and Walker, G. R. (1963).

Journal of the Amlerican ,fedical Association, 186, 1065.Hardy, J. D., et al. (1970). Jfournal of 7horacic and Cardiovascular Surgery,

60, 411.Hugh-Jones, P. (1967). Builletin de Physio-Patholo.'ie Respiratoire, 3, 419.Hutchin, P., Freezor, M. D., Walker, E. L., and Peters, R. M. (1971).

Journal of Thoracic and Cardiovascuilar Surgery, 61, 476.Juvenelle, A. A., Citret, C., Wiles, C. E., and Stewart, J. D. (1951). Journal

of Thoracic Suirgerv, 21, 111.Munro, A., et al. (1971). British Medical Journal, 3, 271.Organ Transplant Registry (1971). American College of Surgery/National

Institutes of Health, Chicago, Illinois.Pines, A., Raafat, H., Siddiqui, G. M., and Greenfield, J. S. B. (1970).

British Medical Journal, 1, 663.Sheil, A. G. R., et al. (1971). Lancet, 1, 359.Stevens, P. M., Johnson, P. C., Bell, R. L., Beall, A. C., and Jenkins,

D. E. (1970). New England Journal of Medicine, 282, 245.Veith, F. J. (1970). Yournal of Thoracic and Cardiovascular Surgery, 60, 423.West, J. B. (1960). Journal of Applied Physiology, 15, 976.West, J. B. (1963). Lancet, 2, 1055.West, J. B., and Hugh-Jones, P. (1959). Journal of Applied Physiology,

14, 743.Wildevuur, C. R. H., and Benfield, J. R. (1970). Annals of Thoracic Surgery,

9, 489.

Ophthalmic Manifestations of the Battered-baby Syndrome

BRIAN HARCOURT, DAVID HOPKINS

British Medical Journal, 1971, 3, 398-401

Summary

Eleven battered babies who had ocular manifestations oftheir abuse are presented. Eight of these suffered apermanent impairment of visual function. Ten hadextensive intraocular haemorrhage, and the importanceof this physical sign in the diagnosis of the syndrome andin the development of a consequent visual handicap isemphasized.

Introduction

The battered-baby syndrome occurs in young children whohave suffered physical trauma at the hands of their parents orguardians. Affected children often have severe permanentphysical, mental, and emotional disabilities, and some die as aresult of the abuse. It is clearly of the utmost importance thatthe diagnosis is never overlooked, and the characteristic asso-ciation of some or all of the following features has been foundmost helpful: (1) the child is usually less than 2 years of age;(2) the general condition of the child is often indicative ofneglect; (3) there is often a disproportionate amount of softtissue injury; (4) there may be evidence that the injuries haveoccurred at different times, and, in particular, radiographicskeletal survey may show that a number of bony fractures are indifferent stages of resolution; (5) the parents' or guardians'history is inadequate and incompatible with the demonstrableinjuries; and (6) there is often a history of multiple admissionsto hospital, and characteristically no new lesions appear duringthe child's stay in hospital (modified from Birrell and Birrell,1968).

Leeds General Infirmary, Leeds LSl 3EXBRIAN HARCOURT, F.R.C.S., D.O., Consultant Ophthalmic SurgeonDAVID HOPKINS, F.R.C.S., D.O., Senior Registrar in Ophthalmology

Despite detailed descriptions of external, visceral, skeletal,craniocerebral, and psychiatric findings in affected children(Caffey, 1946; Silverman, 1953; Kempe et al., 1962; Griffithsand Moynihan, 1963; McCort and Vaudagna, 1964; Cameronet al., 1966; Isaacs, 1968; Sussman, 1968) little attention hashitherto been directed to the ophthalmic manifestations. It istherefore our purpose to present the ocular findings in 11 youngchildren who fulfil the diagnostic criteria of the syndrome so asto draw further attention to this important aspect of the disorder,demonstrating that in some cases severely defective vision maybe a principal feature of a surviving child's permanent disability.

Case Reports

Tables have been used in order to present a summary of theprincipal general manifestations (Table I) and of the ophthalmicmanifestations (Table 1I) in all the patients examined in thisstudy. The ophthalmic examinations were carried out atintervals ranging from a few days to three years after the majorepisode of trauma, and the progress of most of the patients has

TABLE i-Case Histories: General Manifestations

Diagnostic Criteria CerebralManifestations

Bone Injury

5 6~ + d + aSvr

76 Skull Other E".O

I1 2 + + + + + + + Severe215 + + + + +3 18 + + + + + +4 5 + + + + Moderate5 6 + + +IS6 10 + + + + + 1

7 7 + + + + + Severe8 9 + + + + + Mild9 2 + + + + + + +10 1.1 + + + +11 10 + + + + + + 3



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journal papers and · bronchography (which had suggested widespread basal bronchiec-tasis)...

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